BMS-708163 is a potent selective and orally bioavailable inhibitor of γ-secretase with IC50 value of 0.3nM [1].
The cleavage of amyloid precusor protein APP by γ-secretase causes the production of Aβ40 and Aβ42, which are cytotoxic and cause AD. In vitro assay shows BMS-708163 inhibits the formation of Aβ40 and Aβ42 in H4-8Sw cells. It also inhibits the human recombinant CYPs in vitro with IC50 value of 20μM. Notch receptor is another substrate of γ-secretase. The inhibition of Notch signal pathway results in some side effects. It is shown that the activity of BMS-708163 to inhibit Notch is 190-fold weaker than to APP. In female rats, oral administration of BMS-708163 significantly reduces the production of Aβ in plasma and brain at 10mg/kg and 100mg/kg. In addition, BMS-708163 also reduces Aβ in brain and CSF in male beagle dogs [1].
References:
[1] Gillman KW, Starrett JE Jr, Parker MF, Xie K, Bronson JJ, Marcin LR, McElhone KE, Bergstrom CP, Mate RA, Williams R, Meredith JE Jr, Burton CR, Barten DM, Toyn JH, Roberts SB, Lentz KA, Houston JG, Zaczek R, Albright CF, Decicco CP, Macor JE, Olson RE. Discovery and Evaluation of BMS-708163, a Potent, Selective and Orally Bioavailable γ-Secretase Inhibitor. ACS Med Chem Lett. 2010 Mar 22;1(3):120-4.
